This project proposes to continue studies of temporal trends in HIV incidence and associated risk factors among a cohort of uninfected injection drug users (IDUs). We will also characterize the natural history of injection drug use and drug-related morbidity and mortality, including that caused by hepatitis C virus (HCV) infection, while we initiate important research on uptake of HCV care and treatment among IDUs. Since 1988, we have maintained a cohort of -1000 IDUs, among whom annual HIV incidence is -2% and attrition is low at 10%. Although 90% of our cohort is HCV-infected, only 1% have received HCV treatment. Building upon 15 years of collective experience studying the health effect of injection drug use, our specific aims are: 1) To evaluate temporal trends in HIV incidence, and determine period-specific risk factors and attributable risks associated with illicit drug use and sexual behaviors in a cohort of male and female HIV-seronegative IDUs. Using hierarchical modeling, we will also identify relative and attributable risks associated with macro-level risk factors (e.g., neighborhood social disadvantage, heroin purity) vs. individual-level HIV risk factors. 2) To characterize the natural history of illicit injection drug use, including behavioral and sociodemographic factors associated with initiation, relapse and cessation., taking into account cohort and period effects across the lifespan using Cox and Poisson regression. 3) To determine incidence and temporal trends in morbidity and mortality among HIV seronegative IDUs associated with illicit drug use and co-morbid conditions (e.g., HCV, heart disease, depression) compared to a parallel cohort of HIV-infected IDUs, to differentiate between morbidity related to HIV and highly active antiretroviral therapy vs. drug use itself. 4) To determine HCV treatment eligibility among HCV-infected IDUs and identify individual and environmental barriers associated with access and utilization of HCV treatment. We will also pilot three case management interventions aimed at increasing utilization of HCV treatment among treatment-eligible IDUs using a case-crossover design. To meet the above aims, we plan to recruit an additional 400 HIV-seronegative IDUs to maintain-1000 IDUs under active follow-up over 5 year. HIV serology and self-reported data on HIV risk behaviors will be collected semi-annually using ACASI. In addition to meeting the above aims, we will also store remaining sera in a repository for 10 independently funded collaborations and potential studies of emerging pathogens. In meeting the above aims, this study will inform the design of innovative, targeted and effective structural interventions to create "enabling environments" that may reduce the incidence of HIV and drug use and increase uptake of new HCV treatments as new therapies become available.